The new compounds according to this invention are inhibitors of histone deacetylase (HDAC). Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P. A., et al., J. Nat. Cancer Inst. 92 (2000) 1210–1216. More specifically, WO 98/55449, U.S. Pat. No. 5,369,108, WO 01/38322, WO 01/70675, and WO 02/22577 report alkanoyl, alkylenyl, alkenylenyl, benzyl, and cinnamyl hydroxamates with HDAC inhibitory activity.
Transcriptional regulation is a major event in cell differentiation, proliferation, and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target DNA segments. Nucleosomal integrity is regulated by the acetylation status of the core histones. In a hypoacetylated state, nucleosomes are tightly compacted and thus are nonpermissive for transcription. On the other hand, nucleosomes are relaxed by acetylation of the core histones, with the result being permissiveness to transcription. The acetylation status of the histones is governed by the balance of the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently, HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490–1495).